Research findings in mice by a Michigan scientist raise the possibility that the cancer-promoting effects of the drug DES, a synthetic estrogen once prescribed for an estimated 2 million pregnant women, might affect not only the women's female offspring -- known as "DES daughters" -- but also the granddaughters.
The concern about "DES granddaughters" stems from surprising studies by Dr. Bruce Walker, a professor of anatomy at Michigan State University. Walker found an increase in cancers of the reproductive organs that occurred late in life in the daughters of mice treated with DES during pregnancy. He also found an increase in such cancers in the granddaughters of treated mice -- animals that had never themselves been exposed to the drug.
Walker's findings have not yet been confirmed by other researchers. DES-caused cancers generally do not appear until after puberty, and most of the nation's DES daughters are still only in their middle to late thirties and do not have adult children. "Just because it happens in mice, you can't say it's going to happen in humans," said a spokeswoman for the National Cancer Institute.
Walker said he is frustrated by such arguments. "It applies to mice. We don't know if it applies to people," he said. "But does that justify ignoring it, or should you take precautions?"
DES, or diethylstilbestrol, was widely prescribed to prevent miscarriages from the 1940s until the 1970s. Since 1971, it has been implicated in several hundred cases of clear cell adenocarcinoma, a rare but serious cancer of the vagina and cervix, affecting the daughters of women who took the drug during pregnancy. Use of DES in pregnant women was banned by the Food and Drug Administration in 1971.
University of Chicago researchers reported this year in The New England Journal of Medicine that DES daughters appear to have about a 1 in 1,000 chance of developing the cancer. Of the 519 cases reported to a national registry by mid-1985, 91 percent were found in women between the ages of 15 and 27, with a median age of 19. The number of cases reported nationally peaked in 1975, and has declined gradually since then.
With the declining numbers of cancers, public interest and funding for DES research have also waned. But some researchers, including Walker, continue to wonder whether DES daughters will have additional illnesses during or after menopause, when hormone levels change and cancers often develop.
A number of studies of DES daughters have found a higher-than-average incidence of reproductive problems, such as miscarriages, premature deliveries, ectopic pregnancies and infertility. Some have also found an increase in reproductive tract abnormalities in DES sons. And one study by Dartmouth physicians found about a 50 percent increase in breast cancer in the DES mothers themselves -- the women who took the drug during pregnancy.
Walker's findings in mice are of more than passing interest because he has shown in several studies that when DES is given to pregnant mice, its effects on their female offspring mimic many of the problems found in human DES daughters. Female mice exposed to the drug before birth show changes in the types of cells lining the vagina and cervix similar to the changes seen in exposed women. They also show reduced fertility and an increase in spontaneous abortions and stillbirths.
Unlike DES daughters, the mice exposed to DES before birth show no increase in cancer rates until they reach old age -- about two years. In a 1983 study, Walker compared cancer rates in 143 such DES-exposed female mice raised to old age with 64 controls. He found 14 adenocarcinomas of the uterus and five adenocarcinomas of the cervix in the exposed mice. None were found in the controls, and Walker said such tumors are virtually nonexistent in normal mice.
Walker then raised a group of mouse "DES granddaughters" to old age. In 40 such granddaughters, which he calls DES-lineage mice, he found 10 adenocarcinomas of the uterus and five cystadenocarcinomas of the ovary. No such tumors were found in a group of controls.
Walker is conducting further experiments to explore how DES might exert an effect across two generations. One possibility is that the drug might have caused mutations in the genes of eggs in the ovaries of "DES daughter" mice, eventually affecting their offspring.
Another is that it might have disrupted hormonal control of the reproductive system both of the DES mother, during her pregnancy, and of the developing DES daughter mouse in her womb. If the DES daughter mouse's hormonal system was permanently damaged, that in turn could have affected development of her offspring, putting them at risk for reproductive tumors.
To test the two theories, Walker said he is now transplanting embryos from DES-daughter mice into normal, unexposed mice. He is also performing a mirror-image experiment, transplanting embryos from unexposed mice into DES daughters. Comparing the two groups of granddaughters should help establish whether the increased cancer rate is genetic or results from an altered hormonal environment.
For human DES daughters, the National Cancer Institute recommends a pelvic examination at least once a year, including a Pap smear, careful palpation, and visual inspection of the cervix and vagina after use of an iodine solution to stain the tissue. Some women may need tissue biopsies, more frequent examinations, or use of a special viewing instrument called a colposcope.